Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis
Authors: Dina F. Ahram, Tze Y. Lim, Juntao Ke, Gina Jin, Miguel Verbitsky, Monica Bodria, Byum Hee Kil, Debanjana Chatterjee, Stacy E. Piva, Maddalena Marasa, Jun Y. Zhang, Enrico Cocchi, Gianluca Caridi, Zoran Gucev, Vladimir J. Lozanovski, Isabella Pisani, Claudia Izzi, Gianfranco Savoldi, Barbara Gnutti, Valentina P. Capone, William Morello, Stefano Guarino, Pasquale Esposito, Sarah Lambert, Jai Radhakrishnan, Gerald B. Appel, Natalie S. Uy, Maya K. Rao, Pietro A. Canetta, Andrew S. Bomback, Jordan G. Nestor, Thomas Hays, David J. Cohen, Carolina Finale, Joanna A.E. van Wijk, Claudio La Scola, Olga Baraldi, Francesco Tondolo, Dacia Di Renzo, Anna Jamry-Dziurla, Alessandro Pezzutto, Valeria Manca, Adele Mitrotti, Domenico Santoro, Giovanni Conti, Marida Martino, Mario Giordano, Loreto Gesualdo, Lada Zibar, Giuseppe Masnata, Mario Bonomini, Daniele Alberti, Gaetano La Manna, Yasar Caliskan, Andrea Ranghino, Pierluigi Marzuillo, Krzysztof Kiryluk, Grażyna Krzemień, Monika Miklaszewska, Fangming Lin, Giovanni Montini, Francesco Scolari, Enrico Fiaccadori, Adela Arapović, Marijan Saraga, James McKiernan, Shumyle Alam, Marcin Zaniew, Maria Szczepańska, Agnieszka Szmigielska, Przemysław Sikora, Dorota Drożdż, Malgorzata Mizerska-Wasiak, Shrikant Mane, Richard P. Lifton, Velibor Tasic, Anna Latos-Bielenska, Ali G. Gharavi, Gian Marco Ghiggeri, Anna Materna-Kiryluk, Rik Westland, Simone Sanna-Cherchi
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. Background Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. Methods We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234). Results We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. Conclusions We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.